SFEBES2018 APPLIED PHYSIOLOGY WORKSHOP GPCRS: hotspots and complexes (3 abstracts)
Icahn School of Medicine at Mount Sinai, New York, USA.
Pituitary hormones have long been thought solely to regulate single targets. Challenging this paradigm, we found that both anterior and posterior pituitary hormones, including FSH, had other functions in physiology. We have shown that FSH regulates skeletal integrity, and, more recently, find that FSH inhibition reduces body fat and induces thermogenic adipose tissue in wild type mice, phenocopying genetic haploinsufficiency for the FSH receptor. A polyclonal antibody raised against a short, receptorbinding epitope of FSHβ was found not only to rescue bone loss postovariectomy, but also to display marked antiobesity and probeiging actions. Questioning whether a single agent could be used to treat two medical conditions of public health importance osteoporosis and obesity we developed two further monoclonal antibodies against computationally defined receptorbinding epitopes of FSHβ. We show that both monoclonal antibodies reduce body weight and fat mass and cause beiging in mice on a high-fat diet. They also increase cortical thickness and trabecular bone volume, and microstructural parameters, in shamoperated and ovariectomized mice, noted on microcomputed tomography, as well as inhibit osteoclastic bone resorption and stimulate osteoblastic bone formation. These effects were exerted in the absence of alterations in serum estrogen in wild-type mice. Our study provides the framework for the future development of FSHbased therapeutics that could potentially target both bone and fat.
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Liu et al., Nature, 2017.
Ji et al., PNAS, 2018.